Zhong Sijia, Wang Zihan, Yang Jiaxi, Jiang Di, Wang Kewei
Department of Gastrointestinal Surgery, the First Hospital of China Medical University, Shenyang, 110001, Liaoning Province, China.
Department of Oral Implantology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, 110122, China.
Heliyon. 2024 Sep 7;10(18):e37613. doi: 10.1016/j.heliyon.2024.e37613. eCollection 2024 Sep 30.
Oxaliplatin (OXA)-based therapy is effective in the treatment of multiple cancers. However, primary or acquired OXA resistance remains an emerging challenge for its clinical application. Ferroptosis is an iron-dependent mode of cell death that has been demonstrated to play an essential role in the chemoresistance of many drugs, including OXA. In particular, dysregulation of SLC7A11-GPX4, one of the major antioxidant systems of ferroptosis, was found in the OXA resistance of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). In addition, Nrf2, the upstream regulator of GPX4 and many other antioxidant factors, is also involved in the OXA resistance of CRC and HCC. Inhibition of SLC7A11-GPX4 or Nrf2 by genetic deletion of pharmaceutical inhibition could significantly reverse OXA resistance. Long noncoding RNA (lncRNA) also participates in chemoresistance and ferroptosis of cancer cells. Specifically, LINC01134 promotes the recruitment of Nrf2 to the promoter of GPX4, thereby exerting transcriptional regulation of GPX4, which eventually increases the OXA sensitivity of HCC through upregulation of ferroptosis. On the other hand, a novel lncRNA DACT3-AS1 sensitizes gastric cancer cells to OXA through miR-181a-5p/sirtuin 1(SIRT1)-mediated ferroptosis. Therapies based on ferroptosis or a combination of OXA and ferroptosis enhancers could provide new therapeutic insights to overcome OXA resistance. In the present review, we present the current understanding of ferroptosis-related OXA resistance, highlight ferroptosis pathogenesis in OXA chemoresistance, and summarize available therapies that target OXA resistance by enhancing ferroptosis.
基于奥沙利铂（OXA）的疗法在多种癌症的治疗中有效。然而，原发性或获得性OXA耐药性仍然是其临床应用中一个新出现的挑战。铁死亡是一种铁依赖性细胞死亡模式，已被证明在包括OXA在内的许多药物的化疗耐药中起重要作用。特别是，在结直肠癌（CRC）和肝细胞癌（HCC）的OXA耐药中发现了铁死亡的主要抗氧化系统之一SLC7A11-GPX4的失调。此外，GPX4和许多其他抗氧化因子的上游调节因子Nrf2也参与了CRC和HCC的OXA耐药。通过基因缺失或药物抑制来抑制SLC7A11-GPX4或Nrf2可显著逆转OXA耐药。长链非编码RNA（lncRNA）也参与癌细胞的化疗耐药和铁死亡。具体而言，LINC01134促进Nrf2募集到GPX4的启动子，从而对GPX4进行转录调控，最终通过上调铁死亡增加HCC对OXA的敏感性。另一方面，一种新型lncRNA DACT3-AS1通过miR-181a-5p/沉默调节蛋白1（SIRT1）介导的铁死亡使胃癌细胞对OXA敏感。基于铁死亡或OXA与铁死亡增强剂联合的疗法可为克服OXA耐药提供新的治疗思路。在本综述中，我们阐述了目前对铁死亡相关OXA耐药的认识，强调铁死亡在OXA化疗耐药中的发病机制，并总结了通过增强铁死亡来靶向OXA耐药的现有疗法。
